Dose-response relationships of the objective and subjective antiemetic effects and of different side effects of metoclopramide against cisplatin induced emesis

The graded and quantal responses of metoclopramide (MCL, Paspertin) were studied in patients (17-71 years) treated with cisplatin in combination with other cytostatics. The lowest dose of MCL was 0.125 mg/kg b.w./h i.v. over 2 h as loading infusion, then 0.0625 mg/kg/h over 24 h as the maintenance infusion, the total dose being 1.75 mg/kg per treatment cycle (n = 25). At the same schedule three different higher doses of MCL were run with total doses of 3.5 (n = 44), 7.0 (n = 120), and 14.0 (n = 161) mg/kg per cycle of cisplatin. The mean number of emetic episodes in historical control patients without MCL (n = 41) at the four different doses of cisplatin was 4.2 episodes at 25 mg/m2 of cisplatin, 6.9 episodes at 60 mg/m2, 14.9 at 90, and 21.6 episodes at 120 mg/m2 of cisplatin. The quantitative dose-response curves of the four doses of the emetic agonist cisplatin were shifted to the right by increasing doses of MCL. The following doses of cisplatin for greater than or equal to 95% antiemetic protection (i.e. only 0-2 emetic episodes as clinically sufficient protection) were obtained (at the respective mg/kg of MCL given in brackets): 13 (at 1.75 MCL), 25 (at 3.5 MCL), 42 (at 7 MCL), and 80 (at 14 MCL) mg/m2 of cisplatin, respectively. The MCL dose in order to provide greater than or equal to 95% of the patients against every mg/m2 of cisplatin was about 0.15 (range 0.13-0.18) mg/kg MCL per cycle (i.e. 6.5 mg/m2 of cisplatin are antagonized by 1 mg/kg of MCL).(ABSTRACT TRUNCATED AT 250 WORDS)     

5-Hydroxytryptamine M-receptor antagonism to prevent cisplatin-induced emesis

The administration to the ferret of cisplatin, 10mg/kg (i.v.), caused an intense emetic response that was prevented by ICS 205-930 (0.1 and 1.0 mg/kg i.v.) and metoclopramide (4.0 mg/kg i.v.). Smaller doses of ICS 205-930 (0.01 mg/kg i.v.) and metoclopramide (2.0 mg/kg i.v.) attenuated the emetic response to cisplatin. It is concluded that the potent action of ICS 205-930 against cisplatin-induced emesis is the consequence of a 5-hydroxytryptamine M-receptor antagonism which may also contribute to the antiemetic action of metoclopramide.     

Ondansetron--the first of a new class of antiemetic agents.

The chemistry, pharmacokinetics, adverse effects, stability, compatibility, and dosage of ondansetron hydrochloride are described, and clinical studies of the use of ondansetron for the prophylaxis of nausea and vomiting induced by antineoplastic therapy are reviewed. Ondansetron hydrochloride is a specific antagonist of serotonin type 3 (5-HT3) receptors, both in the chemoreceptor trigger zone and in the GI tract. Peak plasma concentrations of ondansetron occur approximately one hour after an oral dose and 6 to 20 minutes after an i.v. dose. The mean elimination half-life is approximately 3.5 hours in healthy volunteers, but it is extended in elderly patients (mean of 7.9 hours). In clinical trials, ondansetron has been shown to provide excellent control of nausea and vomiting in patients treated with cisplatin. Comparisons of ondansetron with metoclopramide in patients treated with various types of chemotherapy have shown better response rates with ondansetron. Ondansetron has also been shown to be effective in controlling nausea and vomiting in patients receiving cyclophosphamide with an anthracycline and in patients receiving combination therapy with cyclophosphamide, methotrexate, and fluorouracil. Adverse effects appear to be mild and include headache, constipation, diarrhea and transient abnormalities in liver function tests. The dose of ondansetron (as the hydrochloride salt) for the prophylaxis of chemotherapy-induced nausea and vomiting in adults is 0.15 mg/kg i.v. every four hours for three doses, beginning 30 minutes before antineoplastic therapy. The efficacy of ondansetron is comparable to that of metoclopramide, and the adverse-effect profile is much less problematic. The cost of ondansetron is much higher than that of metoclopramide; thus its use should be limited to patients at high risk for metoclopramide-induced adverse effects and patients in whom metoclopramide is ineffective.     

Vagal afferent fibers and peripheral 5-HT3 receptors mediate cisplatin-induced emesis in dogs.

The involvement of visceral afferent fibers and 5-HT3 receptors in the emesis induced by cisplatin was studied in beagle dogs. The emesis induced by cisplatin (3 mg/kg, i.v.) was inhibited by the intravenous administration of ICS205930 (2 x 0.01 or 2 x 0.1 mg/kg) and MDL72222 (2 x 0.5 mg/kg), 5-HT3 receptor antagonists, but not by the intravenous administration of metoclopramide (2 x 0.5 mg/kg), a dopamine D2 receptor antagonist. The cisplatin-induced emesis was also suppressed by the intravenous administration of para-chlorophenylalanine (300 mg/kg/day for 3 days), an inhibitor of 5-HT synthesis. On the other hand, the administration of ICS205930 into the IVth ventricle (2 x 0.01 mg/animal) had no effects on the cisplatin-induced emesis. The cisplatin-induced emesis was completely inhibited by abdominal vagotomy and splanchnicectomy, but not by splanchnicectomy alone. On the contrary, the emesis induced by apomorphine was suppressed by the intravenous (0.1 mg/kg) or intracerebroventricular (0.05 mg/animal) administration of metoclopramide, but not by visceral nerve section. These results strongly suggest that cisplatin evokes emesis mainly by acting on the vagal afferent terminals through the release of 5-HT and that peripheral 5-HT3 receptors are involved in this action.     

Antiemetic activity of ondansetron in acute gastroenteritis

Background : The mechanism of nausea and vomiting associated with gastroenteritis is unknown. The role of 5-HT₃ receptors in emesis associated with gastroenteritis was investigated in paediatric patients.
Methods : A randomized, double-blind, placebo-controlled, parallel-group study was conducted in three groups of 12 patients each, receiving either a single i.v. dose of ondansetron (0.3 mg/kg), metoclopramide (0.3 mg/kg) or placebo (sterile saline). Food was restricted and oral rehydration was administered for 4 h.
Results : During 0–24 h, the number of emetic episodes experienced was significantly greater ( P =0.048) with placebo (mean=5) than ondansetron (mean=2) and the proportion of patients experiencing no emesis was significantly greater ( P =0.039) with ondansetron (58%) than placebo (17%). A numerical difference, in favour of ondansetron, was observed between ondansetron and metoclopramide groups for both of the above parameters. Fewer treatment failures were observed with ondansetron (17%) than placebo (33%) and metoclopramide (42%). More diarrheal episodes were observed in the groups receiving anti-emetic treatment. All three treatments were well tolerated.
Conclusions : Ondansetron, a 5HT₃ receptor antagonist, was significantly superior to placebo in preventing emesis associated with acute gastroenteritis, in paediatric patients. Therefore, serotonin, acting through 5HT₃ receptors, may play a role in this form of emesis.     

The antiemetic efficacy of tropisetron plus dexamethasone as compared with conventional metoclopramide-dexamethasone combination in Orientals receiving cisplatin chemotherapy: a randomized crossover trial

1We report a single-blind randomized crossover trial comparing the efficacy of tropisetron plus dexamethasone (TROPDEX) vs conventional combination of metoclopramide, dexamethasone and diphenhydramine (METDEX) in prevention of acute and delayed vomiting in Chinese patients receiving high dose cisplatin. 2Thirty-six consecutive patients with nasopharyngeal carcinoma were entered into the study, all received cisplatin at a dose range of 60–100 mg/m². Patients were randomized in the sequence of antiemetic regimens used in two consecutive cycles. 3The TROPDEX regimen consisting of tropisetron 5 mg i.v. and dexamethasone 20 mg i.v. given on day 1 of chemotherapy, followed by oral maintenance with tropisetron 5 mg daily and dexamethasone 4 mg twice daily from day 2 to 6. The METDEX regimen consisting of metoclopramide 1 mg kg⁻¹ i.v., dexamethasone 20 mg i.v. and diphenhydramine 25 mg i.v. given before chemotherapy and then 2 hourly for two more doses on day 1, followed by oral metoclopramide 20 mg 6 hourly from day 2 to 6. 4Complete control of acute vomiting was observed in 64% of patients with TROPDEX as compared with 14% with METDEX (P<0.01). While complete plus major control of acute vomiting was observed in 84% with TROPDEX as compared with 58% with METDEX. The mean vomiting episodes on day 1 were 1.4 with TROPDEX as compared with 3.5 with METDEX (P<0.01). There was, however, no significant difference between the two regimens in the control of delayed vomiting. 5When patients randomized to TROPDEX in the second cycle were compared with those with TROPDEX in the first cycle, the antiemetic efficacy was reduced, with mean acute vomiting episodes of 2 in the former compared with 0.8 in the latter (P<0.01). 6The most common adverse effect observed was headache in TROPDEX (27%) and dizziness in METDEX (40%). 7In conclusion, the antiemetic regimen TROPDEX is effective in Chinese patients receiving high dose cisplatin chemotherapy and is well tolerated. It is better than conventional METDEX regimen in the control of acute vomiting, but not in the control of delayed vomiting.     

Antiemetic efficacy of prochlorperazine, haloperidol, and droperidol in cisplatin-induced emesis

The antiemetic efficacy of haloperidol, droperidol, and prochlorperazine in preventing cisplatin-induced emesis was evaluated. Twenty-seven patients receiving 51 courses of cisplatin chemotherapy randomly received antiemetic treatment with prochlorperazine (6 mg/sq m), droperidol (1 mg/sq m), or haloperidol (1 mg/sq m) in a double-blind crossover study. Antiemetics were given by intramuscular injection one hour before beginning cisplatin and every three hours thereafter for a total of six doses. The number of emetic episodes, volume of emesis, and duration of the emetic episodes were monitored by oncology nurses. There were no significant differences in the median number of emetic episodes among antiemetic treatments: 3.5 for prochlorperazine, 4.0 for haloperidol, and 3.0 for droperidol. There were also no significant differences among the antiemetics in the median volume of emesis or the median duration of the emetic episodes. At the doses used in this study, the antiemetic efficacy of prochlorperazine, droperidol, and haloperidol appear to be comparable for patients receiving cisplatin chemotherapy.     

The pharmacokinetics of high dose metoclopramide in patients with neoplastic disease.

High dose metoclopramide infusions (10 mg/kg) were administered to nineteen patients with bronchial carcinoma who were receiving intravenous cyclophosphamide as single agent chemotherapy. Considerable interindividual variability in metoclopramide disposition was observed. Mean clearance was 0.33 +/- 0.13 (s.d.) l h-1 kg-1, mean volume of distribution at steady state was 3.8 +/- 1.2 (s.d.) l/kg and mean elimination half-life was 8.3 +/- 4.4 (s.d.) h. These results were significantly different from mean values previously reported for young healthy volunteers given conventional doses (0.70 l h-1 kg-1, 2.2 l/kg and 2.6 h respectively). Significant correlations were found between serum urea, serum creatinine and metoclopramide clearance. The metoclopramide regimens were well tolerated and, with the exception of two patients, were completely effective in the prevention of nausea and vomiting. To achieve and maintain target serum metoclopramide concentrations of 1 microgram/ml, we now administer a loading infusion of 3.61 mg/kg over 30 min followed by a maintenance infusion of 0.36 mg kg-1 h-1 for 10 h. Cyclophosphamide is normally administered concurrently with the second infusion. For patients with evidence of mild renal impairment, the maintenance infusion rate of metoclopramide hydrochloride should be adjusted according to the predicted individual clearance value; CL (l h-1 kg-1) = 0.57 - [0.036 X urea (mmol/l)].     

The antiemetic profile of Y-25130, a new selective 5-HT3 receptor antagonist.

Y-25130( (+/-)N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-4-methyl-3-oxo-3,4-dihydro - 2H-1,4-benzoxazine-8-carboxamide hydrochloride) is a potent and selective 5-HT3 receptor antagonist free of dopamine receptor blocking activity. This compound was effective against emesis induced in animals by cytotoxic drugs or by total body X-radiation. When given prophylactically, the doses required to completely inhibit cisplatin-induced emesis in dogs and doxorubicin and cyclophosphamide-induced emesis in ferrets were 0.1 and 0.3 mg/kg i.v., respectively. Y-25130, at the dose of 0.3 mg/kg i.v., almost completely inhibited X-radiation-induced emesis in ferrets. When given during emesis, the doses required to completely inhibit cisplatin-induced emesis in dogs and doxorubicin- and cyclophosphamide-induced emesis in ferrets were 0.1 and 0.3 mg/kg i.v., respectively. The i.v. dose of 0.3 mg/kg of Y-25130 was enough to almost completely inhibit cisplatin-induced emesis in dogs for 24 h. From these results, it is suggested that Y-25130 may become an effective antiemetic drug against emesis induced by anticancer therapy.     

Ondansetron: a pharmacoeconomic and quality-of-life evaluation of its antiemetic activity in patients receiving cancer chemotherapy

Ondansetron is more effective than high-dose metoclopramide in the prevention of acute nausea and vomiting due to highly emetogenic chemotherapy, and, unlike metoclopramide, is rarely associated with extrapyramidal effects. Pharmacoeconomic analyses have demonstrated that, in specified clinical settings, ondansetron (8mg 4-hourly for 3 doses or 8mg followed by 1 mg/h for 24 hours) is equally cost-effective as high-dose metoclopramide (3 mg/kg followed by 0.5 mg/kg/h for 8 hours) in the prophylaxis of emesis in patients receiving highly emetogenic chemotherapy, at an acquisition cost 4- or 5-fold higher than that of the metoclopramide regimen. Furthermore, the combination of dexamethasone plus ondansetron has been shown to be more effective than ondansetron monotherapy in controlling emesis. In patients receiving high-dose ( greater than 50 mg/m2) cisplatin-based chemotherapy, antiemetic therapy with ondansetron (8mg intravenously as a single dose) plus dexamethasone (16mg total intravenous dose) was shown to be more cost-effective than the combination of high-dose metoclopramide (11 mg/kg total intravenous dose), dexamethasone (8mg intravenously as a single dose) plus lorazepam (1 to 1.5mg intravenously as a single dose). In a limited number of studies, quality-of-life scores, as assessed using the Rotterdam Symptom Checklist or the Functional Living Index--Emesis instrument, were significantly higher with ondansetron than with other antiemetic agents, including metoclopramide. Together, these results suggest that ondansetron, as an alternative to antiemetic regimens including high-dose metoclopramide, is appropriate cost-effective therapy for the prevention of acute nausea and vomiting in patients receiving highly emetogenic chemotherapy. Ondansetron is effective in controlling acute emesis associated with moderately emetogenic chemotherapy, and its use in this clinical setting may best be reserved for patients who have not responded well to previous antiemetic therapy with more traditional agents. However, poorly controlled emesis can lead to anticipatory nausea and vomiting in subsequent courses of chemotherapy, thus, consideration should also be given to the use of ondansetron in patients receiving moderately emetogenic chemotherapy, although further pharmacoeconomic investigations are required to clarify its use in this clinical setting.     

Cisplatin-induced emesis in the cat: effect of granisetron and dexamethasone

The emetic action of cisplatin was investigated in the cat using a closed circuit video recording system. In initial investigations, cisplatin 3 and 5 mg/kg, i.v. induced emesis over a 2-day period following a latency of 17.6+/-9.6 and 15.6+/-7.8 h, respectively. The anti-emetic efficacy of granisetron and dexamethasone was investigated in the cisplatin 5 mg/kg, i.v.-induced emesis model. In these experiments, cisplatin induced 47.0+/-14.0 and 20.0+/-9.0 retches+vomits on days 1 and 2, respectively, following a latency of 2.4+/-0.4 h. Granisetron (1 mg/kg, i.m.) administered three times per day reduced significantly the retching+vomiting response induced by cisplatin on days 1 and 2 by 100.0% (P<0.05) and 75.0% (P<0.05), respectively; dexamethasone (0.01-1 mg/kg, i.m.) administered three times per day reduced significantly the retching+vomiting response by 68.8-100.0% (P<0.05) and 33.3-100.0% (P<0.05) on days 1 and 2, respectively. The emetic action of cisplatin 7.5 mg/kg, i.v. was also investigated. This dose of cisplatin-induced emesis following a latency of 1.2+/-0.2 h and comprised 119.0+/-20.8 retches+vomits over a 24-h period. Granisetron and dexamethasone antagonized the emesis occurring in the first 3-h period (P<0.05) but were less effective to antagonize the subsequent emetic response (P0.05). The pharmacological sensitivity of low dose cisplatin-induced emesis in the cat is variable but unique and not representative of the clinical situation.     

Antiemetic effects of YM060, a potent and selective serotonin (5HT)3-receptor antagonist, in ferrets and dogs.

YM060, (R)-5-[(1-methyl-3-indolyl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole hydrochloride, is a new serotonin (5HT)3-receptor antagonist. We examined the effects of YM060 on chemotherapeutic agent-, apomorphine- and copper sulfate-induced emesis. Intravenous YM060 potently prevented cisplatin (10 mg/kg, i.v.)-induced emesis with ED50 values of 0.06 (0.05-0.07) micrograms/kg, i.v. in ferrets. Based on the ED50 values, YM060 was 300, 20 and 100 times more potent than ondansetron, granisetron and the S-isomer of YM060, respectively. The relative potencies of these drugs described above were similar to those in the previously reported 5HT3-receptor antagonism. YM060 given orally also potently inhibited cisplatin (10 mg/kg, i.p.)- and cyclophosphamide (200 mg/kg, i.p.)-induced emesis in ferrets with ED50 values of 0.1 (0.09-0.11) and 0.02 (0.16-0.27) micrograms/kg, p.o., respectively. All tested 5HT3-receptor antagonists including YM060 failed to prevent apomorphine (0.1 mg/kg, s.c.)-induced emesis in dogs and copper sulfate (1%, 10 ml, p.o.)-induced emesis in ferrets. Our data indicate that YM060 is a highly potent inhibitor of chemotherapeutic agent-induced emesis and that the antiemetic effect of YM060 may be depend on 5HT3-receptor antagonism.     

Effect of glucagon on amitriptyline-induced cardiovascular toxicity in rats

The aim of this study was to investigate the effect of glucagon on cardiovascular parameters in anesthetized rat model of tricyclic antidepressant overdose. Toxicity was induced by infusion of amitriptyline 0.94 mg/kg/min until a 40-45% of reduction in mean arterial pressure was observed. Amitriptyline infusion rats were then randomized into three groups. Control group of rats (group 1) received a bolus of 5% dextrose followed by the continuous infusion of dextrose, whereas treatment groups received 1 mg/kg (group 2) or 2 mg/kg (group 3) bolus doses of glucagon followed by continuous infusion (0.1 mg/kg/min) of glucagons for 60 min. Mean arterial pressure, heart rate, and electrocardiogram were recorded. Amitriptyline caused a significant decrease in mean arterial pressure and a prolongation in QRS, yet it did not change the heart rate. High-bolus dose of glucagon (2 mg/kg) followed by glucagon infusion significantly increased mean arterial pressure at 40, 50, and 60 min (P < 0.05) and shortened the prolonged QRS at 50 and 60 min (P < 0.05) when compared with control group. There was also a significant increase in heart rate. In conclusion, bolus doses followed by a continuous infusion of glucagon were found to be effective in reversing the hypotension and QRS prolongation in the rat model of amitriptyline toxicity. Further studies are needed to reveal the exact mechanism of the proposed effect.     

The effect of electroacupuncture as an adjunct on cyclophosphamide-induced emesis in ferrets

The effect of electroacupuncture (EA) on cyclophosphamide-induced emesis in ferrets was studied at acupuncture point Neiguan (P6) with various electrical stimulation parameters (5-100 Hz, 1.5-3 V, 5-20 min, n=6/group). The combination therapy of EA (100 Hz, 1.5 V and 10 min) with the lower doses of ondansetron (0.04 mg/kg), droperidol (0.25 mg/kg) and metoclopramide (2.24 mg/kg) significantly reduced the total number of emetic episodes by 52%, 36% and 73%, respectively, as well as the number of emetic episodes in the first phase as compared to the sham acupuncture control (P<.01). These EA/drug combinations also showed a significant effect in preventing emesis as compared to either EA or drug alone (P<.05). The present study suggests that acupuncture may be useful as an adjunctive therapy in the treatment of chemotherapy-induced emesis.     

Pancopride, a potent and long-acting 5-HT3 receptor antagonist, is orally effective against anticancer drug-evoked emesis.

Pancopride ((+-)N-(1-azabicyclo-[2,2,2]-oct-3-yl)-2-cyclopropylmethoxy-4-ami no-5-chlorobenzamide) is a new potent and selective 5-HT3 receptor antagonist, orally and parenterally effective against cytotoxic drug-induced emesis. In vitro, pancopride displayed high affinity (Ki = 0.40 nM) for [3H]GR65630-labelled 5-HT3 recognition sites in membranes from the cortex of rat brains. In vivo, pancopride antagonized 5-HT-induced bradycardia in anaesthetized rats when administered i.v. 5 min (ID50 = 0.56 microgram/kg) or p.o. 60 min (ID50 = 8.7 micrograms/kg) before 5-HT challenge. A single oral dose (10 micrograms/kg) of pancopride produced a significant inhibition of the bradycardic reflex over an 8-h period. Pancopride dose dependently inhibited the number of vomiting episodes and delayed the onset of vomiting induced by cisplatin in dogs (ID50 = 3.6 micrograms/kg i.v. and 7.1 micrograms/kg p.o.). Pancopride was also effective in blocking mechlorethamine- and dacarbazine-induced emesis. Unlike metoclopramide, pancopride was shown to lack any measurable antidopaminergic activity both in vitro and in vivo. These results support clinical data, indicating that pancopride will be a useful drug for treating cytostatic-induced emesis in humans.     

Metoclopramide as an antiemetic agent in pediatric oncology patients

Metoclopramide (MCP) was used as an antiemetic agent in 11 pediatric oncology patients during 22 courses of cancer therapy including cisplatin, doxorubicin, and other agents. Initial MCP regimens used 2 mg/kg/dose iv prior to and at 1.5, 3.5, 5.5, and 8.5 hours post-chemotherapy. Subsequent dose reduction to 1 mg/kg and addition of diphenhydramine to all regimens has been made to decrease adverse drug effects. Seven of 11 children reported subjective benefit, defined by comparison with previous antiemetic response, comfort, and willingness to continue MCP therapy. MCP effectively reduced the volume of emesis per 24-hour period as compared with volume of emesis recorded following other antiemetics, an observation that should be confirmed in controlled studies of efficacy. Acute dystonic reactions developed in five children, occurring most frequently in those who received 2 mg/kg/dose regimens or consecutive day dosing. These reactions were rapidly reversible with diphenhydramine, but limited patient acceptance of further MCP use.     

Improved benefit/risk ratio of higher-dose metoclopramide therapy during cisplatin-induced emesis

Summary Metoclopramide (Paspertin) was infused intravenously in the high doses of 1.75, 3.5, 7.0, and 14 mg/kg body wt. per treatment cycle as antiemetic therapy for cisplatin-induced emesis (363 cycles, 25–120 mg/m²). The antiemetic potency of metoclopramide increased in a log linear manner, giving from 40% to 95% protection against emesis. Gas-trointestinal motility showed a similar increase, i.e. diarrhoea. In contrast, the extrapyramidal reactions, namely akathisia, rigidity and acute dystonia, did not show a dose-dependent increase in frequency and remained constant over the dose range of 3.5–14 mg/kg per cycle. The results suggest increasing benefit of metoclopramide treatment with increasing doses of the drug.     

Inhibition of cisplatin-induced emesis in the pigeon by a non-psychotropic synthetic cannabinoid

The (+) enantiomer of the synthetic cannabinoid, 7-hydroxy-delta-6-tetrahydrocannabinol, dimethylheptyl homolog (HU-211), possesses significant antimetic efficacy in the pigeon. However, unlike all anti-emetic cannabinoids tested in the past, it is devoid of psychotropic (cannabimimetic) activity. The anti-emetic activity of HU-211 was determined in pigeons given 10 mg/kg i.v. cisplatin, a widely used antitumour agent, which is also a potent emetogenic agent at this dose. This activity was compared with that of delta-1-tetrahydrocannabinol (delta-1-THC). HU-211 pretreatment elicited a dose-related inhibition of cisplatin vomiting, with the optimal dose of HU-211 (2.5 mg/kg) inhibiting emesis by nearly 90%. Delta-1-THC in doses up to 5 mg/kg caused only an insignificant reduction in vomiting. The activity was increased in the presence of cupric chloride (0.8 mg/kg). The optimal dose of delta-1-THC (5.0 mg/kg) with CuCl2 very significantly diminished the total amount of vomitus expelled (up to 90%). However, it failed to inhibit emesis in 50% of all animals tested, did not significantly affect the time of onset of emesis and was highly psychotropic. The optimal dose of HU-211 (2.5 mg/kg) with CuCl2 inhibited emesis by 97%, significantly delayed the time on onset of emesis in the very few animals that did vomit and was completely non-psychotropic. The curve for the antiemetic effect of HU-211 was U-shaped over a narrow dose range. The present report demonstrates that complete separation of psychotropic and antiemetic activities is possible in the cannabinoid series.     

The actions of fentanyl to inhibit drug-induced emesis.

The ability of fentanyl to inhibit drug-induced emesis was investigated in the ferret. Initial studies established that morphine, in small doses (0.025-0.5 mg/kg s.c.), induced emesis in the ferret that decreased at the larger doses of 1 and 2 mg/kg (s.c.). Fentanyl (10-80 micrograms/kg s.c.) failed to induce emesis but in this dose range prevented the emesis induced by morphine (0.5 mg/kg s.c.), apomorphine (0.25 mg/kg s.c.), copper sulphate (100 mg/kg intragastric) and cisplatin (10 mg/kg i.v.). The antiemetic effects could be obtained in the absence of sedation or motor impairment. The antagonism by fentanyl of apomorphine-, copper sulphate- and cisplatin-induced emesis was inhibited by naloxone (0.1 or 0.5 mg/kg s.c.). It is concluded that fentanyl exerts a broad spectrum of actions to inhibit drug-induced emesis. An autoradiographic study of the binding of [3H]DAGO to the brainstem of the ferret indicated high densities of mu recognition sites in the area postrema, nucleus tractus solitarius, dorsal motor nucleus of the vagus, reticular medulla and other sites. The results are discussed in terms of balanced facilitatory and inhibitory opioid systems, regulating emesis and that the antiemetic actions of fentanyl reflect an important, although not necessarily an exclusive, action at mu opioid receptors.     

Pharmacokinetics of intact cisplatin in plasma. Infusion versus bolus dosing

Plasma levels of total platinum, total filterable platinum and intact cisplatin were monitored in 4 patients who received cisplatin in a regimen consisting of 20 mg/m² by i.v. bolus followed immediately by 80 mg/m² by 6 h infusion. Baseline pharmacokinetic parameters were obtained from a previous study in which 100 mg/m² of cisplatin was administered by a single i.v. bolus. These baseline pharmacokinetic parameters were used in an attempt to predict the pharmacokinetic behavior of cisplatin in the present study. The results demonstrated close agreement between observed and predicted plasma level-time profiles and the area under the plasma concentration-time profiles for cisplatin. The ratios of the various platinum species in plasma over the time course of the study were also consistent with those previously reported. These findings suggest that at a dose of 100 mg/m², the pharmacokinetics of cisplatin and its conversion to other species in plasma are independent of dosage schedule. Since 100 mg/m² is a relatively high dose of cisplatin, it is likely that this approach is applicable to other doses and schedules, and ultimately might prove useful in designing optimum cisplatin dosage regimens.